Proteasome inhibition induces neurite outgrowth through posttranslational modification of TrkA receptor.
The ubiquitin-proteasome pathway regulates many biological processes, including protein degradation, receptor endocytosis, protein sorting, subnuclear trafficking and neuronal differentiation. While proteasome inhibition is known to induce neurite outgrowth, the signaling mechanisms that mediate these effects have not been defined. In this study, we investigated the underlying mechanisms that link proteasome inhibition with neurite generation. We found that the proteasome inhibitors, MG132 and lactacystin, induced neurite outgrowth and also activated extracellular signal-regulated kinase/mitogen activated protein kinase and phosphatidylinositol-3-kinase/AKT pathways. These proteasome inhibitors also induced phosphorylation and ubiquitination of TrkA receptors, indicating that proteasome inhibition activates the major pathways of TrkA signaling. However, in contrast to nerve growth factor stimulation, which induces internalization of surface TrkA receptors, proteasome inhibitor-induced neurite outgrowth did not require TrkA receptor internalization. These results indicate that the ubiquitin-proteasome system regulates neurite formation through posttranslational modification of TrkA receptors.
Song
Eun Joo
EJ
Bioanalysis and Biotransformation Research Center, Life Sciences Research Division, Korea Institute of Science and Technology, P.O. BOX 131, Cheongryang, Seoul 130-650, Republic of Korea.
Hong
Hye-Min
HM
Yoo
Young Sook
YS
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D007976:Leupeptins / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009414:Nerve Growth Factors / Q000378:metabolism*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D009414:Nerve Growth Factors; D061988:Proteasome Inhibitors; C067713:lactacystin; D020917:Receptor, trkA; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; D000111:Acetylcysteine